After adding exogenous renin to plasma from both hypertensive patients and patients with renal insufficiency, the rate of angiotensin generation is faster than that in plasma of normotensive control subjects. These differences are not related to endogenous renin or endogenous renin substrate. Preliminary results from our laboratory indicate that acetone soluble neutral lipids extracted from normal human plasma inhibit the in vitro reaction between renin and renin substrate; less inhibition occurs with neutral lipids extracted from uremic plasma. The purpose of the present proposal is to identify the acetone soluble renin inhibitor in normal human plasma and to determine if this inhibiting lipid is less concentrated in plasma of hypertensive patients and uremic patients. A deficiency of this inhibiting factor might account for the increased reactivity of renin in hypertensive and uremic plasma. Renin inhibitor concentrations will also be compared in patients with low, normal, and high renin essential hypertension to determine if varying concentrations of a circulating renin inhibitor might contribute to this renin status. After identifying and purifying the inhibitor, appropriate enzyme kinetic studies will be carried out to determine the mechanism of inhibition. In addition, a physiologic role for the renin inhibiting factor will be evaluated by determining its potential to lower blood pressure in an experimental model of renin dependent hypertension. The identification of a naturally occurring circulating inhibitor of renin and the demonstration of alterations of renin inhibitor concentrations in plasma of patients with hypertension or renal disease will add a new dimension to current understanding of the renin-angiotensin system.